Preclinical efficacy and clinical safety of clinical-grade nebulized allogenic adipose mesenchymal stromal cells-derived extracellular vesicles.

Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) turn out to be a promising source of cell-free therapy. Here, we investigated the biodistribution and effect of nebulized human adipose-derived MSC-EVs (haMSC-EVs) in the preclinical lung injury model and explored the safety of nebulized haMSC-EVs in healthy volunteers. DiR-labelled haMSC-EVs were used to explore the distribution of nebulized haMSC-EVs in the murine model. Pseudomonas aeruginosa-induced murine lung injury model was established, and survival rate, as well as WBC counts, histology, IL-6, TNF-α and IL-10 levels in bronchoalveolar lavage fluid (BALF) were measured to explore the optimal therapeutic dose of haMSC-EVs through the nebulized route. Twenty-four healthy volunteers were involved and received the haMSC-EVs once, ranging from 2 × 108 particles to 16 × 108 particles (MEXVT study, NCT04313647). Nebulizing haMSC-EVs improved survival rate to 80% at 96 h in P. aeruginosa-induced murine lung injury model by decreasing lung inflammation and histological severity. All volunteers tolerated the haMSC-EVs nebulization well, and no serious adverse events were observed from starting nebulization to the 7th day after nebulization. These findings suggest that nebulized haMSC-EVs could be a promising therapeutic strategy, offering preliminary evidence to promote the future clinical applications of nebulized haMSC-EVs in lung injury diseases.

N-Acetylcysteine modulates acute lung injury induced by Pseudomonas aeruginosa in rats.

1. In critically ill patients, Pseudomonas aeruginosa-induced pneumonia and the lung injury associated with infection are major causes of mortality. The aim of the present study was to evaluate the protective properties of N-acetylcysteine (NAC) in rats infected with P. aeruginosa and the role of nitric oxide synthases (NOS) protein in this process. 2. Pneumonia was induced in rats by infecting them with P. aeruginosa intratracheally. One group of rats was treated with NAC (150 mg/kg per day, i.p., for 7 days). An untreated group served as the control. Samples were collected both before (0 h) and after infection (24 h). Bacterial loads in lung tissue, the lung wet : dry (W/D) ratio and pulmonary vascular permeability were assessed. Total cell and polymorphonuclear leucocyte cell counts in bronchoalveolar lavage fluid were determined. The expression of inducible (i) NOS and endothelial (e) NOS protein was analysed and correlated with indices of lung injury using Pearson's correlation analysis. 3. Bacterial load, lung injury indices and NOS expression increased after infection. Pretreatment with NAC mitigated lung injury although it did not significantly change bacterial loads. Furthermore, NAC treatment increased eNOS protein expression, but decreased iNOS expression, in lung tissues after infection. The expression of iNOS protein was positively correlated with indices of lung injury, whereas there was a negative correlation between eNOS expression and lung injury indices. 4. N-Acetylcysteine modulated P. aeruginosa-induced lung injury in rats. The results suggest that this effect maybe due to regulation of iNOS and eNOS protein expression by NAC.